Assessment of the feasibility of human amniotic membrane stem cell-derived cardiomyocytes in vitro.

Myocardial infarction (MI) is a leading cause of death worldwide, resulting in extensive loss of cardiomyocytes and subsequent heart failure. Inducing cardiac differentiation of stem cells is a potential approach for myocardial regeneration therapy to improve post-MI prognosis. Mesenchymal stem cells (MSCs) have several advantages, including immune privilege and multipotent differentiation potential. This study aimed to explore the feasibility of chemically inducing human amniotic membrane MSCs (hAMSCs) to differentiate into cardiomyocytes in vitro. Human amniotic membrane (AM) samples were obtained from routine cesarean sections at Far Eastern Memorial Hospital. The isolated cells exhibited spindle-shaped morphology and expressed surface antigens CD73, CD90, CD105, and CD44, while lacking expression of CD19, CD11b, CD19, CD45, and HLA-DR. The SSEA-1, SSEA-3, and SSEA-4 markers were also positive, and the cells displayed the ability for tri-lineage differentiation into adipocytes, chondrocytes, and osteoblasts. The expression levels of MLC2v, Nkx2.5, and MyoD were analyzed using qPCR after applying various protocols for chemical induction, including BMP4, ActivinA, 5-azacytidine, CHIR99021, and IWP2 on hAMSCs. The group treated with 5 ng/ml BMP4, 10 ng/ml Activin A, 10 µM 5-azacytidine, 7.5 µM CHIR99021, and 5 µM IWP 2 expressed the highest levels of these genes. Furthermore, immunofluorescence staining demonstrated the expression of α-actinin and Troponin T in this group. In conclusion, this study demonstrated that hAMSCs can be chemically induced to differentiate into cardiomyocyte-like cells in vitro. However, to improve the functionality of the differentiated cells, further investigation of inductive protocols and regimens is needed.

Association of health information technology-driven multidisciplinary approaches with low-density lipoprotein cholesterol target achievement in patients with an acute coronary syndrome.

Objective: Controlling of low-density lipoprotein cholesterol (LDL-C) in patients with acute coronary syndrome (ACS) remains a challenge. Health information technology (HIT) is increasingly being applied to close quality gaps in chronic illness care. The aim of this study was to perform a qualitative review of the association of implementing HIT on lipid management processes of care and LDL-C goal attainment in patients with ACS. Method: Eligible patients with a discharge diagnosis of ACS from January 2018 to December 2021 at a tertiary medical center were retrospectively reviewed. An HIT system with a multidisciplinary approach including initiating high-intensity statin therapy, periodic laboratory follow-up, titration of lipid-lowering agents, patient education, patient-level and system-level interventions involving database monitoring and outreach by centralized care teams was introduced in October 2018. Electronical medical records including data on medications and laboratory findings at discharge and within 1 year were compared before and after implementing the HIT system. Results: A total of 2001 ACS patients (average age 63 ± 12.7 years, 79.66 % men) were analyzed. The LDL-C < 70 mg/dL goal attainment rates (36.52 %, 53.57 %, 59.22 %, 62.18 % in 2018-2021) and medium serum LDL-C levels (80.5 mg/dL, 68 mg/dL, 65 mg/dL, 64 mg/dL in 2018-2021) significantly improved within 6 months (2018 as the reference, all p<0.001). The LDL-C attainment rate at 12 months also steadily increased (53.80 %, 61.82 %, 64.21 % in 2019-2021, p = 0.019). Most of the patients switched to a high-intensity statins regimen at discharge (0.57 %, 63.67 %, 72.41 %, 84.44 %, in 2018-2021, p<0.001 with 2018 as the reference), with low adverse event rates. The maintenance rates of high-intensity statin regimens at 12 months continued to improve (41.36 %, 49.04 %, 61.39 % in 2019-2021, p<0.001). Conclusions: Efforts to control LDL-C should be increased in ACS patients by initiating and intensifying statin treatment earlier. Our results confirmed that a team-based strategy with HIT improved LDL-C target achievement for most patients with ACS.

Non-ST-segment elevation myocardial infarction with non-obstructive coronary arteries due to a type-A thymoma: A case report.

Introduction: Myocardial infarction with non-obstructive coronary arteries (MINOCA) has become an increasingly recognized subgroup in patients with acute myocardial infarction, with a recent cohort study reporting a prevalence of 8.8%. This report describes a patient who presented with non-ST-segment elevation myocardial infarction (NSTEMI) due to an incidental anterior mediastinal mass. Case presentation: An 80-year-old woman presented to our emergency department with a chief complaint of progressive shortness of breath associated with retrosternal chest pain for one day duration. Computed tomography (CT) angiogram of the chest was conducted, which revealed an anterior mediastinal mass. Upon admission, the patient developed an acute episode of recurrent severe chest pain, which was diagnosed as an NSTEMI. Emergent cardiac catheterization was performed because of unstable vital signs; however, the results showed no evidence of atherosclerotic changes in the major coronary arteries, compatible with the diagnosis of MINOCA. The mediastinal mass was later confirmed to be a type A thymoma on CT-guided biopsy. Conclusion: Myocardial infarction in patent coronary arteries due to an anterior mediastinal mass is rare. Further studies are needed to standardize the diagnosis and management protocols for the potential etiologies of MINOCA.

S100A8/A9 Enhances Immunomodulatory and Tissue-Repairing Properties of Human Amniotic Mesenchymal Stem Cells in Myocardial Ischemia-Reperfusion Injury.

Paracrine factors of human mesenchymal stem cells (hMSCs) have the potential of preventing adverse cardiac remodeling after myocardial infarction (MI). S100A8 and S100A9 are calcium-binding proteins playing essential roles in the regulation of inflammation and fibrous tissue formation, and they might modulate the paracrine effect of hMSCs. We isolated human amniotic mesenchymal stem cells (hAMSCs) and examined the changes in the expression level of regulatory genes of inflammation and fibrosis after hAMSCs were treated with S100A8/A9. The anti-inflammatory and anti-fibrotic effects of hAMSCs pretreated with S100A8/A9 were shown to be superior to those of hAMSCs without S100A8/A9 pretreatment in the cardiomyocyte hypoxia/reoxygenation experiment. We established a murine myocardial ischemia/reperfusion model to compare the therapeutic effects of the conditioned medium of hAMSCs with or without S100A8/A9 pretreatment. We found the hearts administered with a conditioned medium of hAMSCs with S100A8/A9 pretreatment had better left ventricular systolic function on day 7, 14, and 28 after MI. These results suggest S100A8/A9 enhances the paracrine therapeutic effects of hAMSCs in aspects of anti-inflammation, anti-fibrosis, and cardiac function preservation after MI.

Modulators of Mortality Benefit From Peri-Angioplasty Adjunctive Tirofiban in Patients With ST-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention.

BACKGROUND: Studies investigating the modulators of mortality benefit conferred by peri-angioplasty glycoprotein IIb/IIIa inhibitors in ST-elevation myocardial infarction (STEMI) are still lacking.Methods and Results:A prospective database (n=1,025) of consecutive cases undergoing primary percutaneous coronary intervention for STEMI was retrospectively analyzed. For patients in Killip class I, II or III, IV, the multivariate-adjusted hazard ratios of 30-day all-cause mortality associated with adjunctive tirofiban were 3.873 (95% CI 0.504-29.745; P=0.193), 0.550 (95% CI 0.188-1.609; P=0.275), and 0.264 (95% CI 0.099-0.704; P=0.008), respectively. The P value for a linear trend was 0.032. Patients who had a body mass index (BMI) within 22.9-25.0 kg/m2had a significant benefit from tirofiban (adjusted HR 0.344; 95% CI 0.145-0.814; P=0.015) compared to other BMI groups. The P value for a quadratic trend was 0.012. A novel Killip-BMI score (KBS = 2.5 × Killip category - | BMI - 24 |) was calculated to select the beneficial population. A KBS ≥2 was associated with significant mortality benefit, whereas a KBS <0 predicted increased 30-day mortality with tirofiban use. CONCLUSIONS: Survival benefit from peri-angioplasty tirofiban therapy for STEMI was positively correlated with the Killip class. Tirofiban should be used cautiously in either underweight or overweight patients. The novel KBS used in this study can guide peri-angioplasty use of adjunctive tirofiban in patients with STEMI undergoing primary angioplasty.

Clinical Feasibility of Biofunctionalized Magnetic Nanoparticles for Detecting Multiple Cardiac Biomarkers in Emergency Chest Pain Patients.

BACKGROUND: The rapid diagnosis of acute myocardial infarction (AMI) is a clinical and operational priority in emergency departments. Serial serum levels of cardiac biomarkers play a crucial role in the evaluation of patients presenting with acute chest pain, so that an accurate and rapidly responsive assay of cardiac biomarkers is vital for emergency departments. METHODS: Immunomagnetic reduction (IMR) has been developed for rapid and on-site assays with a small sample volume. IMR kits for three biomarkers [myoglobin, creatine kinase-MB (CK-MB), and troponin-I] have been developed by MagQu Co., Ltd., Taiwan (US patent: US20190072563A1). In this study, we examined correlations between IMR signals and biomarker concentrations. The measurement threshold of the IMR kits, dynamic ranges, interference tests in vitro, and reagent stability were tested. Clinical cases were included with serial IMR measurements to determine the time course and peak of IMR-measured cardiac biomarkers after AMI. RESULTS: The correlations between IMR signals and biomarker concentrations fitted well to logistic functions. The measurement thresholds of the IMR kits (1.03 × 10-8 ng/mL for myoglobin, 1.46 × 10-6 ng/mL for CK-MB, and 0.08 ng/mL for troponin-I) were much lower than the levels detected in the patients with AMI. There was no significant interference in vitro. The peak times of IMR-detected myoglobin, CK-MB, and troponin-I after AMI were 8.2 hours, 24.4 hours, and 24.7 hours, respectively. CONCLUSIONS: IMR is an accurate and sensitive on-site rapid assay for multiple cardiac biomarkers in vitro, and may play a role in the early diagnosis of AMI. Clinical trials are needed.

Multiobjective Evolution of Biped Robot Gaits Using Advanced Continuous Ant-Colony Optimized Recurrent Neural Networks.

This paper proposes the optimization of a fully connected recurrent neural network (FCRNN) using advanced multiobjective continuous ant colony optimization (AMO-CACO) for the multiobjective gait generation of a biped robot (the NAO). The FCRNN functions as a central pattern generator and is optimized to generate angles of the hip roll and pitch, the knee pitch, and the ankle pitch and roll. The performance of the FCRNN-generated gait is evaluated according to the walking speed, trajectory straightness, oscillations of the body in the pitch and yaw directions, and walking posture, subject to the basic constraints that the robot cannot fall down and must walk forward. This paper formulates this gait generation task as a constrained multiobjective optimization problem and solves this problem through an AMO-CACO-based evolutionary learning approach. The AMO-CACO finds Pareto optimal solutions through ant-path selection and sampling operations by introducing an accumulated rank for the solutions in each single-objective function into solution sorting to improve learning performance. Simulations are conducted to verify the AMO-CACO-based FCRNN gait generation performance through comparisons with different multiobjective optimization algorithms. Selected software-designed Pareto optimal FCRNNs are then applied to control the gait of a real NAO robot.

Lipid lowering therapy in patients with atherosclerotic cardiovascular diseases: Which matters in the real world? Statin intensity or low-density lipoprotein cholesterol level? ‒ Data from a multicenter registry cohort study in Taiwan.

OBJECTIVE: Whether a low-density lipoprotein cholesterol (LDL-C) goal is essential in secondary prevention is still being debated. The aim of our study was to investigate whether achieving particular LDL-C level goals is associated with the reduction in the risk of major adverse cardiac events (MACEs) in patients with atherosclerotic cardiovascular diseases (ASCVD) on statin therapy. METHODS AND RESULTS: From January 2010 to August 2014, a total of 4099 patients with ASCVD in the Taiwan Secondary Prevention for patients with AtheRosCLErotic disease (T-SPARCLE) registry were analyzed. The risk of a MACE was lower in patients with LDL-C level under control at < 100 mg/dL by statins than in patients with LDL-C level ≥100 mg/dL whether on statin therapy (hazard ratio [HR] 1.66, 95% confidence interval [CI] 1.04‒2.63, p = 0.03) or not (HR 2.04, 95% CI 1.06‒3.94, p = 0.03). In multivariate Cox model analyses, statin intensity had no significant predictive value, and LDL-C ≥ 100 mg/dL was associated with a slight but not significant trend toward increased risk of MACEs (HR 1.41, 95% CI 0.96‒2.07, p = 0.08). CONCLUSIONS: For patients with ASCVD on statin therapy guided by a target-driven strategy, failure to control LDL-C levels to < 100 mg/dL was associated with higher risk of MACEs. Statin intensity alone had no significant impact on the risk of MACEs after multivariate adjustment.

Rapid Early Triage by Leukocytosis and the Thrombolysis in Myocardial Infarction (TIMI) Risk Score for ST-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: An Observational Study.

The clinical utility of leukocytosis in risk assessment for ST-elevation myocardial infarction (STEMI) is still unclear. We aim to demonstrate the prognostic value of leukocyte counts independent from traditional risk factors and the TIMI risk score (TRS) for STEMI and to propose a practical model comprising leukocyte count for early triage in STEMI undergoing primary angioplasty. A prospective database (n = 796) of consecutive STEMI cases receiving primary angioplasty at a tertiary medical center was retrospectively analyzed in the period from February 1, 2007 through December 31, 2012. Primary endpoints were 30-day and 1-year mortality. Propensity score-adjusted Cox regression models and subdivision analysis were performed. Leukocytosis group (n = 306) had higher 30-day mortality (5.9% vs 3.1%, P = 0.048) and 1-year mortality (9.2% vs 5.1%, P = 0.022). After adjustment by propensity score and TRS, leukocyte count (per 10/µL) was an independent predictor of 1-year mortality (HR: 1.086, 95% CI: 1.034-1.140, P = 0.001). Subdivision analysis demonstrated the correlation between leukocytosis and higher 1-year mortality within both high and low TRS strata (divided by 4, the median of TRS). Additionally, 24% (191 out of 796) of patients were characterized by nonleukocytosis and TRS < 4, having 0% of mortality rate at 1-year follow-up. In conclusion, leukocyte count is an independent prognostic factor adding incremental value to TRS for STEMI. Nonleukocytosis in conjunction with TRS < 4 identifies a large patient group at extremely low risk and thus provides rapid early triage for STEMI patients undergoing primary PCI. This finding is worth validation in the future.

Early left ventricular free-wall rupture in non-STEMI never to be neglected.

As the most dramatic and fatal complication, left ventricular free-wall rupture (LVFWR) used to present in approximately 3% of patients with acute myocardial infarction. After the introduction of primary percutaneous coronary intervention, the incidence of LVFWR decreased but remained approximately 1.7%. Left ventricular free-wall rupture occurs in patients with transmural myocardial infarction, which is almost exclusively ST elevation myocardial infarction (STEMI). This condition carries a high mortality as a result of hemopericardium and cardiac tamponade. Left ventricular free-wall rupture rarely occurs in patients with non-ST-elevation myocardial infarction, but the risk of it cannot be ignored. This case describes early development LVFWR after non-ST-elevation myocardial infarction to evoke high vigilance of clinicians to this condition.

2-[3-[2-[(2S)-2-Cyano-1-pyrrolidinyl]-2-oxoethylamino]-3-methyl-1-oxobutyl]- 1,2,3,4-tetrahydroisoquinoline: a potent, selective, and orally bioavailable dipeptide-derived inhibitor of dipeptidyl peptidase IV.

Dipeptidyl peptidase IV (DPP-IV) inhibitors are expected to become a new type of antidiabetic drugs. Most known DPP-IV inhibitors often resemble the dipeptide cleavage products, with a proline mimic at the P1 site. As off-target inhibitions of DPP8 and/or DPP9 have shown profound toxicities in the in vivo studies, it is important to develop selective DPP-IV inhibitors for clinical usage. To achieve this, a new class of 2-[3-[[2-[(2S)-2-cyano-1-pyrrolidinyl]-2-oxoethyl]amino]-1-oxopropyl]-based DPP-IV inhibitors was synthesized. SAR studies resulted in a number of DPP-IV inhibitors, having IC(50) values of <50 nM with excellent selectivity over both DPP8 (IC(50) > 100 microM) and DPP-II (IC(50) > 30 microM). Compound 21a suppressed the blood glucose elevation after an oral glucose challenge in Wistar rats and also inhibited plasma DPP-IV activity for up to 4 h in BALB/c mice. The results show that compound 21a possesses in vitro and in vivo activities comparable to those of NVP-LAF237 (4), which is in clinical development.